Project 4: The need for mathematical models to extrapolate O3 exposure-response data between different animal species and different exposure scenarios is well recognized. Significant progress has been made in modeling the spatial distribution of O3 dose during simple continuous exposures in mature respiratory systems, but little work has been done on simulating episodic exposures, and no research exists on modeling O3 dose distribution in an immature developing respiratory system. The primary objective of this work is to model the exposure-dose relationship in the respiratory system of a rhesus monkey infant as he undergoes episodic inhalation of O3 between the ages of 1 month to 6 months. A young nonhuman primate was selected for study because it will lead to a better understanding the effect that O3 has on human infants and children. A second objective of this project is to determine and to compare dose-response relationships in the nasal cavities and in the tracheobronchial tree. This will allow us to extrapolate monkey exposure-response data to children and also to judge whether or not the nose can be used as a sentinel of health effects in the lower respiratory tract. The specific aims of the project are to: 1 ) develop a one-dimensional single-path model that is capable of simulating longitudinal dose distribution; 2) develop three-dimensional diffusion models that simulate the spatial distribution of O3 at specific sites such as the nasal cavities and isolated airway bifurcations; 3) integrate and validate the site-specific diffusion models with the single-path model; 4) apply the integrated model to establish nasal and lower airway dose-response relationships for site-specific histochemical endpoints; and 5) extrapolate the exposure-response observed in the young monkey to that in the human child. This project will have strong interactions with the other components of this Program-Project. Anatomical, histological, and biochemical data generated in Projects 1-3 will be crucial for estimating input parameters to the model simulations, for validating models, and for developing dose-response relationships. The Computational Core will be essential for implementing numerical solutions to the model equations and for developing statistical analyses that establish dose-response relationships and evaluate model precision.